According to the prior art, diseases of the central nervous system, more particularly dementias comprising mild to moderate forms of Alzheimer's disease, are treated by means of acetylcholinesterase inhibitors (e.g., donepezil). For the treatment of moderate to severe Alzheimer's disease, use is made of NMDA receptor antagonists.
The development of Alzheimer's disease is caused by neurodegenerative processes with cell loss in the cortex or regions of the brain. Cholinergic nerves, including the areas innervated thereby, are especially affected. In the early stage of the disease, the glutamatergic system is disrupted. As a result of an excessive calcium influx into the neurones, in the long term neurodegeneration can occur. As the most important glutamatergic synapse, the NMDA complex has a central role to play here. Inhibition of the complex by means of a selective antagonist can protect the neuronal areas from excitatory damage.
Signs of Alzheimer's disease are strongly enlarged ventricles, microscopically detectable plaques, and neurofibrillary tangles. The clinical picture is usually characterized by memory loss and by a gradual decline in personality and intellect. In this respect, the goal of an Alzheimer's treatment is to alleviate personal suffering and thus to counteract social isolation. A curative therapy is currently not available. In this respect, it is desirable to delay appropriately the development of the dementia, which usually proceeds progressively. A palliative therapy has the following goals: improvement of cognitive function, minimization of noticeable neurological behavioral patterns, delaying of the progression of the disease, and prevention of seizure symptoms.
According to the prior art, it is known that NMDA receptor antagonists are suitable as neuroprotectors, by preventing the damaging effect of glutamate at NMDA receptors. The group of the NMDA receptor antagonists include, for example, substances such as MK 801, dextromethorphan, ketamine, memantine, amantadine, dextrorphan, felbamate, acamprosate, MRZ 2/579, phencyclidine, aptiganel, and these are a possibility both as individual substances and as mixtures or as physiologically compatible salts thereof, for example hydrochlorides, citrates, maleates, etc.
It is known that the use of NMDA receptor antagonists is limited especially as a result of psychomimetic secondary effects; in this respect, the widespread use thereof has not been seen to date. Especially important in the treatment of Alzheimer's patients is the NMDA receptor antagonist memantine (3,5-dimethyl-9-aminoadamantane) or the hydrochloride thereof. Memantine is approved for the treatment of moderate to severe Alzheimer's disease. The medication is available in Germany under the name Axura®. The drug is available in the form of oral drops for ingestion or as film-coated tablets. The administration of the medication must be carried out only under the supervision of a carer, and the dose of active ingredient has to be increased stepwise over a period of several weeks in order to minimize in particular the secondary effects described for the treatment of moderate to severe Alzheimer's disease, such as, inter alia, hallucinations, disorientation, dizziness, headaches, and fatigue. After the starting phase, the medication must also be strictly administered once in the morning and once in the afternoon (drops) or, when using the film-coated tablets, at the same time every day.
This strict therapy schedule and the associated need for supervision result in the disadvantageous situation of a very high degree of effort or high therapy costs for the care of these patients.
Owing to the abovementioned disadvantages, there is a need for novel therapeutic systems which overcome these disadvantages, more particularly such systems in which the degree of effort for patient care can be reduced.
According to the prior art, it is known that NMDA receptor antagonists can optionally be used in combination with analgesics in topical dosage forms for the treatment of local pain (WO 00/03716 whose United States equivalent is U.S. Pat. No. 7,700,122; WO 03/015 699 whose United States equivalent is United States Publication No. US 2003082214A1 and US 2004076648A1; US 2002/0016319, U.S. Pat. No. 6,194,000). US 2004/0102525, US 2003/0139698, and WO 04/009062 (whose United States equivalent is United States Publication No. US 2004019118A1 and US 2009005459A1); also disclose the administration of NMDA receptor antagonists. WO 04/106275 (whose United States equivalent is United States Publication No. US 2007010507A1 and US 2007048385A1), discloses specific salts of NMDA receptor antagonists.
However, the dosage forms of the prior art are not suitable, or only suitable to a limited extent, for establishing, after topical administration, systemic plasma concentrations of NMDA receptor antagonists which achieve a sufficient pharmacological effect for a sufficient duration. With respect to transcutaneous permeability, no experimental data are disclosed in the prior art.
However, in the prevention or treatment of diseases of the central nervous system, it would be especially desirable to have specifically dosage forms which can maintain pharmacologically effective plasma concentrations over a comparatively long period (e.g., 12 h, 24 h, or longer), not least because, in such cases, the degree of effort for care personnel to care for patients might be reduced.